Ecstasy (primarily containing MDMA) use continues to be major public health problem, especially among young adults. Animal studies suggest that ecstasy is a selective serotonin neurotoxin. However, the effects of ecstasy use on the human brain continue to be understudied. Studies examining cognitive consequences suggest vast individual differences, especially in executive functioning. One possible reason for this variability in ecstasy-related cognitive sequelae is individual variation in baseline serotonin functioning, caused in part by polymorphisms in the serotonin transporter gene (SLC6A4), which is associated with serotonin signaling and serotonin-related diseases. For example, a polymorphism in the promoter region of SLC6A4 (5-HTTLPR) has been associated with cognitive function and brain structure in healthy and depressed adults. Additionally, polymorphism in the variable number of tandem repeats within intron 2 (STin2) of SLC6A4 has been associated with executive functioning in depressed adults. Thus far, results reporting the effects of 5-HTTLPR genotype on neurocognition in ecstasy users are inconsistent. This discrepancy may be due, in part, to the moderating effects of brain-derived neurotrophic factor (BDNF) genotype on SLC6A4 functional consequences and insufficient SLC6A4 genotyping.Furthermore, no studies to date have examined whether SLC6A4 and BDNF genotypes explain individual variability in the effects of ecstasy on brain structure in regions underlying memory, mood and executive functioning. Hence, our primary aim is to determine whether ecstasy use, in combination with genotypes associated with low serotonin signaling, predicts poorer cognitive function and frontolimbic structural abnormalities in young adult ecstasy users, after controlling for polydrug use. To do this, we will combine data from 50 ecstasy users, 50 MJ users (to be newly enrolled in the current proposal) and 50 normal controls (who are already enrolled in a pilot imaging genetics study, PI: Medina). All three groups (N=150) will be administered a psychological and neuropsychological battery and DNA samples will be collected. Based on 5-HTTLPR genotype (balanced for S vs. L/L carriers), 30 young adults from each group will undergo a high-resolution magnetic resonance imaging brain scan. The direct and indirect relationships between ecstasy use, SLC6A4 and BDNF genotypes, cognitive functioning, and frontolimbic structures will be examined. Hence, the current proposal will provide a better understanding of the neurocognitive consequences of ecstasy use and will determine whether SLC6A4 and BDNF genotypes help explain individual differences seen in the consequences of repeated ecstasy use. Ultimately, information gained from this study will help advance genetically targeted biologically based treatments aimed at improving neurocognitive functioning and reducing drug use in young adults. More globally, this study will contribute to the larger knowledge base about how variations in serotonin-associated genes may explain individual differences in susceptibility to and consequences of the numerous serotonin-related diseases. PUBLIC HEALTH RELEVANCE: This project will increase our understanding of the links between genetic variations that affect serotonin signaling, ecstasy (MDMA) consumption, and brain function in young adults. The data will be critical for explaining individual differences in susceptibility for ecstasy-induced thinking problems and brain structure abnormalities. This information will help tailor drug prevention and biologically based intervention programs.